Alterations in the phosphorylation and/or degradation of insulin receptor substrate 1 (IRS-1) produced by burn injury may be responsible, in part, for burn-induced insulin resistance. Specifically, the reduction in glucose transport in skeletal muscle following burn injury may be secondary to altered abundance and/or phosphorylation of IRS-1. We propose that altered serine phosphorylation of IRS-1 following burn injury, mediated by the activation of the stress kinases (p38, MAPK, or SAPK intermediate pathways) by cytokines, such as interleukin-6 (IL-6) or Tumor Necrosis Factor [TNF], down-regulates IRS-1 functions through several mechanisms. Phosphorylation can alter IR/IRS1 interaction as well as IRSI/PI 3-kinase interaction. Moreover, the abundance of IRS-1 is a major determinant of insulin signaling, and the degradation of IRS-1 is controlled, in part, through altered IRS-1 ser/thr phosphorylation, e.g., by an mTOR-dependent pathway. Therefore, we propose that burn injury may increase the turnover of IRS-1. We believe that the best way to further characterize and explore the metabolic etiology of impaired glucose tolerance and the "insulin-resistance" associated with severe burn injury is via an integrated set of studies in human subjects that are complemented and extended by more invasive and mechanistically-focused investigations using murine burn models. The latter will be exploited to define possible cellular loci of insulin function and action that might be causally responsible for the metabolic alterations and abnormalities observed in the clinical setting and would serve as a basis for the rational design of interventions aimed at minimizing the untoward consequences of impaired glucose metabolism and homeostasis. Therefore, the specific aims are: (1) Determine in vivo skeletal muscle glucose transport/phosphorylation and protein synthesis/catabolism under the effects of insulin resistance of burn injury; (2) Determine stress kinase activities after injury; and (3) Determine the phosphorylation sites on IRS-1.